12-substituted-6h-dibenz(b,f)(1,4)oxazocin-11(12h) ones



United States Patent ()flice Patented Dec. 22, 1970 3,549,621 1Z-SUBSTITUTED-6H-DIBENZ[b,f][1,4] OXAZOCIN-11(12H) ONES Harry Louis Yale, 4 New York Ave., New Brunswick,

NJ. 08901, and Ervin Richard Spitzmiller, 6 Seymore Ave., Rte. 37, Highland Park, NJ. 08904 No Drawing. Filed Apr. 29, 1968, Ser. No. 725,174 Int. Cl. C07d 87/54 US. Cl. 260239.3 9 Claims ABSTRACT OF THE DISCLOSURE This invention relates to 12-substituted-6H-dibenz- [b,f][1,4]oXazocin-11(12H)ones and their salts, which may be used to relieve cardiac arrythmia and which may be produced by reaction of the anion of a ring substituted or unsubstituted 6H-dibenz[b,f] [1,4] oxazocin-l 1 12H) one with an aminoalkyl halide, or alternatively, by reaction of the anion of a ring substituted or unsubstituted 6H-dibenz[b,f] [1,4]oxazocin-11(12H)one first with a haloalkyl halide to give the intermediate haloalkyl derivative which is then treated with an amine to give the desired aminoalkyl compound.

SUMMARY OF THE INVENTION This invention relates to 12-substituted-6H-dibenz [b,f] [1,410xazocin-11 (12H)ones which have the formula Nlwer alkylene and to acid addition salts thereof.

The symbols in Formula I and in the succeeding discussion represent the substituents which follow: R represents hydrogen or any of the four halogens of which chlorine, bromine and fluorine are preferred, in that order.

R represents hydrogen, any of the four halogens, preferably chlorine or bromine, trihalomethyl groups such as trifluoromethyl, straight and branched chain lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, trihalomethoxy, such as trifluoromethoxy, trihalomethylmercapto, such as trifluoromethylmercapto, and lower alkyl groups such as methyl, ethyl,

propyl, isopropyl, butyl, isobutyl, t-butyl, amyl and the are amino, dimethylamino, diethylamino, dipropylamino, methyl(ethyl)amino, di(p-hydroxyethyDamino and the like.

The

group may also form a heterocyclic radical. The symbols R may together represent the carbon (and hydrogen) and the oxygen, sulfur or nitrogen atoms which, with the nitrogen atom in the above group, form a 5, 6- or 7-membered nitrogen heterocyclic containing not more than one hetero atom in addition to the nitrogen already shown in the group. These heterocyclic radicals may also bear one" to three of the substituents represented by R or one of the following: hydroxy lower alkyl such as hydroxymethyl, Z-hydroxyethyl or the like, hydroxy-lower alkoxy-lower alkyl such as 2-(2-hydroxyethoxy)ethyl or the like, alkanoyloxy-lower alkyl (up to about 14 carbo'iis in the alkanoyl group) such as Z-heptanoyloxyethyl, carbo-lower alkoxy such as carbomethoxy, carboethoxy, carbopropoxy or the like, or 2-(alkanoyloxy-lower alkoxy)lower alkyl (with up to about 14 carbons in the alkanoyl group) such as Z-(decanoyloxyethoxy)ethyl or the like. I

Illustrative of the heterocyclic radicals represented by are the following: piperidyl; (lower alkyl)piperidyl [e.g., 2-, 3-, or 4-(lower alkyl)piperidyl or 4-(N-lower alkyl)- piperidyl]; di(lower alkyl)piperidyl [e.g., 2,4-, 2,5- or 3,5-di(lower alkyl)piperidyl or 2, 3-, or 4-(N-lower alkyl)-2,3, or 4-(lower alkyl)piperidyl]; (lower alkoxy) piperidyl; [e.g., Z-methoxypiperidyl or 2-methoxypiperidyl]; hydroxypiperidyl; [e.g., 3-hydroxyor 4-hydroxypiperidyl]; aminomethylpiperidyl [e.g., 4-aminomethylpiperidyl]; pyrrolidyl; (lower alkyl)pyrrolidyl, [e.g., 3-methylpyrrolidyl]; di(lower alkyl)pyrrolidyl [e.g., 3,4- dimethylpyrrolidyl]; (lower alkoxy)pyrrolidyl [e.g., 2-methoxypyrrolidyl]; morpholinylf (lower alkyl)morpholinyl [e.g., S-methylmorpholinyl]; di(lower alkyl) morpholinyl [e.g., 3,5-dimethylmorpholinyl]; (lower alkoxy)morpholinyl [e.g. Z-methoxymorpholinyl]; thiamorpholinyl; (lower alkyl)thiamorpholinyl [e.g., 3-methylthiamorpholinyl]; di(lower alkyl)thiamorpholinyl[e.g., 3,5-dimethylthiamorpholinyl; (lower alkoxy)thiamorpholinyl [e.g., 3-methoxythiamorpholinyl]; piperazinyl; (lower alkyl)piperazinyl [e.g., N -methylpiperazinyl]; di(lower alkyl)piperazinyl [e.g., 2,5-dimethylpiperazinyl or 2,6-dimethylpiperazinyl]; (lower alkoxy)piperazinyl [e.g., 2 methoxypiperazinyl]; (hydroxy lower alkyl) piperazinyl [e.g., N -(2-hydroxyethyl)piperazinyl; (alkanoyloxy-lower alkyl)piperazinyl wherein the alkanoyloxy group has up to 14 carbons; [e.g., N -(2-heptanoyloxyethyl) piperazinyl or N (2 dodecanoyloxyethyl)piperazinyl]; (hydroxy-lower alkoxy-lower alkyl)piperazi nyl [e.g., N (2 hydroxyethoxyethyl)piperazinyl]; and (carbo-lower alkoxy)piperazinyl, [e.g., N -(carbometh oxy-, carboethoxy-, or carbopropoxy)piperazinyl; or homopiperazinyl; or N (2 hydroxyethyl)homopiperazinyl [e.g., N -(2-hydroxyethyl)-homopiperazinyl] The particularly preferred compounds are those wherein R is hydrogen, chlorine or trifluoromethyl, R is hydrogen and R is lower alkyl or (R N is N -(hydroxy ethyl)piperazinyl or N-methylpiperazinyl.

The lower alkylene groups in Formula I are straight or branched chain aliphatic hydrocarbon groups such as methylene, ethylene, propylene, isopropylene, butylene, dimethylethylene and the like.

The compounds of Formula I form acid addition salts with various inorganic and organic acids. These salts frequently provide convenient means for separating the product from the reaction mixture in which it is produced or from the solvent in which it is extracted in view of their insolubility in various media. Thus the product may be precipitated in the form of an insoluble salt and convetted, by conventional techniqnes,.to-.the free. base or:

to another salt if desired.

Illustrative salts include the hydrohalides, such as hydrochloride, hydrobromide and hydroiodide, especially the firsttwo, other mineral acid salts such. as phosphate, sulfate, .nitrate, etc., organic acid salts such as Oxalate, tartrate, malate, maleate, citrate, camphorsulfonate,

methanesulfonate, benzenesulfonate, toluenesulfonate, sa-.

licylate, .benzoate, ascorbate, mandelate, pamoate or the like. i I

The new compounds of FormulaI and their physiologically acceptable acid addition salts are useful in the suppression of cardiac arrythmias invarious animal species of which mice, rats and dogs are illustrative. An amount of either the free base or acid addition salt in the range of to 100 mg-./kg., preferably 45 to 65,mg ./kg.,-incorporatedin a conventional form for oral administration, such astablet, capsule or elixir, or in a parenteralform for intramuscular administration may be used to relieve cardiac arrythmias. For example, in mice, a typical range is 45 to 50 mg./kg. orally.

Compounds of Formula I are prepared by reacting a compound of Formula II with an alkali or alkaline n o-on In). R1

The starting materials of Formula II are produced as described in more detail in copend-ing application Ser. No,

627,627, filed Apr. 3, 1967, by first reacting an unsubstituted or R -substituted o-halornethylbenzoic acid alkyl ester with an ,alkali metal salt of an unsubstituted or R substituted o-nitrophenol in an organic solvent such as N,N-dunethylformamide. The resulting alkyl o-[o-nitromylmethylbenzoate is hydrolyzed to obtain the corresponding free benzoic acid. Thenitro group of the latter need to an amino group. This product .is cyclized,

y wi h starting material of Formula II.

following examples are illustrative of the invention.

are on the Centigrade scale.

N,N'-dicyclocarbodiimide in ethyl acet.

- 'EXAMPLE 1 6H-dibenz[b,f] [1,4]oxazocin-l l l2H)-one (a) To 103 g. of sodium o-nitrophenolate, 103 g. of sodium bromide, and 1100 ml. 'of N,N-dimethylformamide is added dropwise 186 g. of methyl 2-chloromethylbenzoate in 450 ml. of N,N-dimethylformamide, and the mixture heated about three hours at 85-90 to giveabout 147 g. of methyl o-[o-nitrophenoxy]methylbenzoate, M.P. abQut-109111.

(b) 'The product from (a), 144 g. suspended in 3600 ml. of 95% ethanol is stirred and refluxed for 10 minutes and then 31 g. of sodium hydroxide in 750 ml. of water is added as rapidly as possible. The refluxing is continued for an additional .10- minutes, the source of heat removed, and 92 ml. ,of concentrated hydrochloric acid in 750ml. of water is added rapidly with vigorous stirring followed by 2100 ml..of water. The mixture is stirred, cooled, and the solid filtered to give about 126 g. of o-[o-nit'rophenoxy] methylbenzoic acid, M.P. about 196198..

(c).The product from (b), 27 g., 200 ml. of 0.5 N sodium hydroxide and 2.0 g. Raney nickelcatalyst are stirred for 10.1 ninutes under nitrogen, and filtered. To the filtrate is added 10 g. of Raney nickel catalyst and the mixture hydrogenated at 50 p.s.i.g. for three hours to give about 22 g. of o-[o-aminophenoxy]methylbenzoic acid, M.P.

(d) The product from (c), 8.0 g., in 750 ml. of anhydrous ethyl acetate is cooled to 18 and 7.2 g. of N,N'- dicyclohexylcarbodiimide in 50 ml. of anhydrous ethyl acetate is added, and the mixture stirred for 24 hours to give about 2.7 g. of 6H-dibenz[b,f] [1,4]oxazocin-11 (12H)-one.

EXAMPLE 2 2-methyl-6H-dibenz [b,f] [1,4]oxazocin-11(l2H)-one By substituting 117 g. of sodium o-nitro-p-cresolate for the sodium o-nitrophenolate in Example 1(a) and then proceeding through steps (b), (c), and (d), there is obtained 2 methyl-6H-dibenz[b,f] [1,4]0xazocin-l 1(12H)- one.

EXAMPLE 3 2-mejthoxy-6H-dibenz [b,f [1,4]oxazocin-1l 12H -one and decomposition of the diazonium compound by water.

. EXAMPLE 4 3'-methyl-6H-dibenz[b,f] [1,4]oxazocin-1 1(12H)-one By substituting 117 g. of sodium o-nitro-rn-cresol for the 7 sodium ,o-nitriphenolate in Example 1(a) and then pro- Example 1(a) and then proceeding through steps (b),

(c), and (d), there is obtained 2-(trifluoromethyl)-6H- dibenz[b,f] [1,4] oxazocin-11(12H)-one.

(b) The o-nitro-p-(trifluoromethyl)phenol is prepared by the reaction of 3-nitro-4-chlorobenzotrifluoride with sodium methoxide to give 3-nitro-4-methoxybenzotrifluoride, followed by cleavage of the latter with pyridine hydrochloride.

EXAMPLE 6 2(N,N-dimethylsulfamoyl)-6H-dibenz[b,f] 1,4] oxazocin-l 1( 12H) -one 3-Methoxy-6H-dibenz[b,f] [1,4]oxazocin-1l(12H)-one By substituting 133 g. of sodium 2-nitro-5-methoxyphenolate for the sodium o-nitrophenolate in Example 1(a) and then proceeding through steps (b), (c), and (d), there is obtained 3-methoxy-6H-dibenz[b,f][1,4]- oxazocin-11(12H)-one.

The Z-nitro-S-methoxyphenol is prepared by the nitration of m-chloroanisole, separation of m-chloro-p-nitroanisole, and then reaction as in Example 1(b).

EXAMPLE 8 2-Acetyl-6H-dibenz [b,f] [1,4] oxazocin-l 1-( 12H -one By substituting 131 g. of sodium o-nitro-p-acetyl phenolate for the sodium o-nitrophenolate in Example 1(a) and then proceeding through steps (b), (c), and (d), there is obtained 2-acetyl-6H-dibenz[b,f][1,4]oxazocin-1l(12H)-one.

The o-nitro-pacetylphenol is obtained by rearrangement of o-nitrophenyl acetate.

EXAMPLE 9 7-Chloro-6H-dibenz [b,f] [l,4]oxazocin-11(12H)-one (a) By substituting 222 g. of methyl 3-chloro-2-ch1oromethylbenzoate for the methyl 2-chloromethylbenzoate in Example 1(a), there is obtained, following the procedure of the steps 1(b), (c), and (d), 7-chloro-6H-dibenz[b,f]- [l,4]oxazocin-11(12H)-0ne.

(b) The chlorination of o-xylene gives 3-chloro-oxylene; dilute nitric acid oxidation of the 3-chloro derivative gives a mixture of products from which m-chloroo-toluic acid is isolated by distillation; the latter, following conversion to the methyl ester and treatment with sulfuryl chloride, gives the required methyl 3-chloro-2-chloromethylbenzoate.

EXAMPLE 10 2-methyl-7-chloro-6H-dibenz[b,f] [1,4]oxazocin- 1 1 12H) -one (a) Employing 222 g. of methyl 3-chloro-2-chloromethylbenzoate, prepared as described in Example 1(b) and sodium-o-nitro-m-cresol and proceeding through steps 1 (a), (b), and ((1), there is obtained 2-methyl-7- chloro-6H-dibenz[b,f] [1,4]oxazocin-11(12H)-one.

EXAMPLE 11 2- (trifluoromethylthio -6H-dibenz [b,f] 1,4] oxazocin- 1 1 12H) -one The chlorination of p-chloromethylthiobenzene gives pchlorotrichloromethylthiobenzene; the latter treated with antimony penatfiuoride antimony trifiuoride-hydrogen fluoride gives p-chlorotrifiuoromethylthiobenzene; the latter is treated with nitric acid-sulfuric acid to give 3-nitro- 4-chloro-(trifiuoromethylthio)benzene. Substituting the 6 latter in the procedure of Example 1(b) gives o-nitro-p- (trifluoromethylthio) phenol. Substituting the sodium salt of the last named compound for the sodium o-nitrophenolate in Example 1(a), and then proceeding as described in the rest of that Example, there is obtained 2- (trifluoromethylthio) 6H dibenz[b,f][l,4]oxazocinl1(l2H)-one.

EXAMPLE 12 12- [Z-(dimethylamino) ethyl] -6H-dibenz[b,f] [1,4]- oxazocin-l 1 12H) -one A solution of 4.9 g. of 6H-dibenz[b,f][1,4]-oxazocinl1(l2H)-one in 30 ml. of dimethylformamide is added dropwise to a stirred suspension of 1.2 g. of 50% sodium hydride in oil dispersion at room temperature, in an atmosphere of nitrogen. During the addition the reaction temperature rises spontaneously to 35. The resulting colorless solution is stirred at room temperature for 30 minutes, then warmed to cooled to 28, and a solution of 4.5 g. of 2-dimethylaminoethylbromide in 30 ml. of toluene is added dropwise. After the addition the reaction mixture is stirred at room temperature for 1 hour, then at 85, filtered and the filtrate concentrated to give 11 g. of a waxy residue. The residue is dissolved in 350 ml. of ether and the ether solution is extracted with a solution of 3 ml. of concentrated (37%) HCl in 25 ml. of water. The aqueous acidic solution is cooled, layered over with 300 ml. of ether and neutralized to a pH of 11 by the addition of solid potassium carbonate. The ethereal solution of the base is separated, dried over magnesium sulfate and the ether is removed leaving a solid residue of about 4.0 g. M.P. about 102-104". It is recrystallized from 35 ml. of ligroin to give about 3.0 g. of product, M.P. 105l06.

EXAMPLE 13 12- 3- (dimethylamino propyl -6H-dibenz [b,f] [1,4] oxazocin-l l 12H) -one To 5 g. of n-butyllithium in 50 ml. of dry hexane is added a ssupension of 11.3 g. of 6H-dibenz[b,f] [1,4]oxazocin-l1(12H)-one in 500 ml. of dry toluene, the whole is stirred for 1 hour at 70, cooled to 30 and 10.0 g. of 3-dimethylaminopropyl bromide in ml. of dry toluene is added dropwise. The mixture is then heated for 16 hours at 85-90" to give about 4.9 g. of product, M.P. 98-99 after recrystallization from hexane.

EXAMPLE 14 12- 2- (diethylamino ethyl] -6H-dibenz [b,f] [1,4] oxazocin-11(l2H)-one Employing the procedure of Example 12 but substituting 2-diethylaminoethyl chloride for the Z-dimethylaminoethyl bromide, there is obtained 12 [2 (diethylamino)ethyl] 6H dibenz[b,f] [1,4]-oxazocin-l1(12H)- one, M.P. 70-72, after recrystallization from petroleum ether (B.P. 30-60).

EXAMPLE 15 12-[2-(diethylamino)ethyl]-6H-dibenz[b,f] [1,4] oxazocin-l l 12H)-one maleate A solution of 1.5 g. of maleic acid in 10 ml. of. dry acetone is added to a solution of 4.2 g. of 12-[2-(diethylamino)ethyl] 6H dibenz[b,f] [1,4]oxazocin 11( 12H)- one in 10 ml. of acetone. The maleic acid salt of 12-[2- (diethylamino)ethyl] 6H dibenz[b,f] [1,4] oxazocin- 1l(12H)-one crystallizes from the solution.

EXAMPLE 16 12-[3-dimethylamino)propyl] -6H-dibenz[b,f] [1,4] oxazocin- 1 l 12H) -one hydrochloride A solution of 4.0 g. of 12 [3 (dimethylamino}propyl] -6H dibenz[b,f][1,4]oxazocin l1(l2H) one in 200 ml. of anhydrous ether is cooled in an ice-water bath and 5.0 ml. of 2.6 N ethereal hydrogen chloride is added, with stirring. The hydrochloride salt separates from solution.

EXAMPLE 17 12[3-(diethylamino)propyl] -6H-dibenzo [b,f] [1,4]

oxazocin-1l(12H)-one EXAMPLE 18 12 3- (bis-hydroxyethyl) amino] propyl-2,9-dibromo- 6H-dibenz [b,f] [1,4] oxazocin- 11 (12H -one (a) Employing the procedure of Example 1(a) but substituting sodium p-bromo-o-nitrophenolate for thesodium o-nitrophenolate and methyl 5 bromo 2 chloromethylbenzoate for the methyl 2-chloromethylbenzoate, there is obtained methyl [4 bromo 2 nitrophenoxy] methyl--bromobenzoate.

(b) The bromination of methyl o-toluate gives methyl- 5-bromotoluate; the latter with sulfuryl chloride in dry chloroform gives methyl 5-bromo-2-chloromethyl benzoate.

(c) When the product from (a) is carried successively through steps 1 (b), 1(c) and 1(d), there is obtained 2,9-dibromo-6H-dibenz[b,f] 1,4]oxazocine-11 (12H)-one.

(d) When the anion of the product from (c), obtained by substituting 8.5 g. of (c) for the 6H dibenz[b,f] [1,4]oxazocin-l1(l2H)-one in Example 12, is treated with 6.3 g. of trimethylene chlorobromide and the mixture is heated for one hour at 85, there is obtained 12 (3 chloropropyl) 2,9 dibromo 6H dibenz [b,f][1,4]oxazocin-ll(12H)-0ne.

(c) When the product from (d) in toluene and 4.2 g. of bis-(hydroxyethyl)amine are heated for 2 hours under reflux, there is recovered via acid extraction as in Example 12, the desired 12 [3 (bis hydroxyethyl)amino] propyl 2,9 dibromo 6H dibenz[b,f] [l,4]oxazocin- 11(l2H)-one.

EXAMPLE 19 2,9-difiuoro-12-[2-(N-homopiperazinyl) ethyl] -6H- dibenz [b,f] [1,4 oxazocin-l l 12H -one Employing the procedure of Example 1(a) but substituting sodium p-fluoro-o-nitrophenolate for the sodium-o-nitrophenolate and methyl 2 chloromethyl-S- fiuorobenzoate for the methyl 2 chloromethylbenzoate there is obtained methyl o [4 fiuoro 2 nitrophenoxy]methyl-S-fluorobenzoate.

(b) Esterification of S-nitro-o-toluic acid with methanol concentrated sulfuric acid gives methyl S-nitro-otoluate; the latter is reduced to the amine, the amine is diazotized, and the diazonium derivative converted to the fluoroborate, and the fluoroborate decomposed to give methyl 5 fiuoro o toluate. The latterwith sulfuryl chloride in dry chloroform gives methyl 2 chloromethyl- 5-fiuorobenzoate.

(c) When the product from (a) is carried successively through steps 1(b), 1(c), and 1(d) there is obtained 2,9 difluoro 6H dibenz[b,f] [l,4]oxazocin 11(12H)- one. I

(d) When the anion of the product from (0) obtained by, substituting 6.1'- g. of (c) for the 6H dibenz[b-,f] [1,4]oxazocin-l l l2H)-one-in Example 12 is treatedwith 6.3 g. of ethylene chlorobromide and the mixture ,is heated for one hour at 85 there is obtained 2,9 difiuoro- 12 [2 chloroethyll- 6H '-.dibenz[b,f] [1,4] oxazocin- 11(12H)-one. I p

(e) When the product frame-(d), 250 ml. of ethyl methyl ketone, 2.6 g. of.,so diurn; iodide, and 4.0 g. of homopiperazine are stirred and heated under refluxior 18 hours, and the crude product fractionally crystallized,

(12H) one as the more soluble-component and bis- N ,N 12 [2,9 difluoro 6H dibenz[ b,f] (1,4)oxazocin-1l(l2H)-one ethyl)homopiperazine. I

I EXAMPLE 20 L v v 2,3,4,5-tetrafluoro-6H-dibenz[b,f] [1,41oxazocin- I (a) Employing the procedure of Example 1(a) but employing sodium 2 nitro 3,4,5,6 tetrafluorophenolate for the sodium o-nitrophenolate for the sodium o-nitrophenolate there is obtained methyl o-[3,4,5,6-tetrafluoro- 2-nitrophenoxy]methylbenzoate.

(b) The nitro 3,4,5,6 tetrafluorophenol is obtained by reacting nitropentafluorobenzene with sodium methoxide, separating the desired 2 nitro 3,4,5,6 tetrafluoroanisole from the isomeric 4 nitro 2,3,5,6 tetrafluoroanisole, and cleaving the former vwith aluminum chloride to give 2 nitro 3,4,5,6 tetrafluorophenol.

(c) When the product from (a) is carried successively through steps 1(b), 1(c), and 1(d), there is obtained 2,3,4,5 tetrafiuoro 6H dibenz[b,f] [1,4]oxazocin- 11(12H)one. m

EXAMPLE 21 Z-methyll 2- 5- morpholinyl) pentyl) ]-6H-dibenz (a) When the product from Example 2 is converted to the anion as in Example 12 but the Z-dimethylaminoethyl bromide is replaced by 5-(morpholinyl)pentyl bromide there is obtained the desired compound.

(b) By heating 122.5 g. of 5-chloropentanol and 174 g. of morpholine under reflux for five hours and working up the reaction mixture there is obtained 5- (morpholinyl) pentanol; treatment of the latter with 48% "hydrobrom-ic acid at gives 5-(morpl'iolinyDpentyl bromide hydro bromide; the latter dissolved in water and the solution neutralized with potassium carbonate gives '5-(morpholinyl)-pentyl bromide as'a pale yellow oil.

EXAMPLE 22 By employing the appropriately substituted 6H-dibenz [b,f] [1,4]oxazocin 11(12H) one and the appropriate aminoalkyl halide, prepared as in Example 21- (b), the

Substitueut in BEE-dibenz [b,f][1,4]oxazocin-11(12H)0ne Substituent in 12-position R2 R 12 Aminoalkyl halide I CH2C 2 CHzCHz Z-CHzO H 1 CH -N N(CH2)3C1 CHgN N(CH2 )3 f v CHiCHg 'CHgCHg omen, omen? 1 cm enthol chi l I(()H 0112011 CHzC r I Substltueut in GH-dlbenz [b,f][1,4]xazoeln-1l (12H)one R2 R n Aminoalkyl halide Substituent in l2-position CH2CH2 CHzCHi 2-CF H 1 S (CHmBr S N(CH cflzcz cfiacfia CH2CH2 CH2CH2 2-(CH:)2NSO2 H 1 N(CH2)3C1 N(CH2) CH2CH2 CHZCH? CH; CH3 CH2( JH CHr-H 3-CH3O H 1 CH2 N (CHmCl 0 H2 N (CHM- CH2-C H CHz-CH H; C O CHzCHz O CI'I2CH'; 2-CH (J H 1 (EH 0 (l-N N (CHmCl CH 0 CJ-N liq-(CH CHtCHz CHzCHz CH O-CHC H2 CHzO CH-C H2 7-01 H 1 N(CH2) 201 N (CHz)z CHzC H2 C1120 H: 2-CH; 7-Cl l (CH3)2N(CH2)4C1 (CHa)2N(CH)4- 2-CF S H 1 (CHmNCHzCHCHzCl (CH3)2NCHzCHCHz- Ha CH5 2,3-(CHa): H 2 (C2H5)2NCH2CHC1 (CzH5)2NCH2CH- CH3 (7H3 1,2,3,4-F4 H 4 (CH3)2N(CH2)3C1 (CH;)2N(CH2)3 CHzCHz CHzCHz H H 1 CH N N(C H2301 CH N mom CHgCHz CHzCHz CH2CH2 CHzCH H H 1 HO CHzCHz-N N(CH2) C1 HO CHzCHr-N N(CH CH2CH2 EXAMPLE 23 12 [3 [N (Z-hydroxyethyl)piperazinyl]propyl] -2-(trifiuorornethyl) -6H-dibenz [b,f] [1,4] oxazocine-l 1 (12H) one EXAMPLE 24 12 [3-[N -(2-heptanoyloxyethyl)piperazinyl1pfopyl]-2- (trifluoromethyl) -6H-dibenz [b,f [1,41oxazocine-l 1 (121-1) -one When the product from chloride are stirred and refluxed in is obtained the desired compound.

EXAMPLE 25 3-methoxypyrrolidinylethyl chloride Example 23 (b) and heptanoyl dry chloroform, there When 2-methoxysuccinic acid and acetic anhydride are refluxed for three hours and the mixture is concentrated to dryness there is obtained Z-methoxysuccinic anhydride. When the anhydride and Z-aminoethanol are heated in a of the product from Example 5 r sealed tube at 200, there is obtained 2-(3-methoxysuccinimidyl)ethanol. The latter is hydrogenated at 200 and 2000 p.s.i. of hydrogen to give 3-methoxypyrr0lidinylethanol. The ethanol derivative and thionyl chloride in dry chloroform give the desired 3-methoxypyrrolidinylethyl chloride.

EXAMPLE 26 When the product from Example 24(a) and 4 N ethanolic methylamine are kept at; room temperature for 72 hours in a sealed vessel and then heated for 3 hours at 5060, there is obtained the desired compound.

EXAMPLE 27 12- [3- (amino propyl] -2- (trifiuoromethyl) -6H-dibenz [b,f] [1,41-oxazocin-1l 12H) -one dium hydroxide gives the desired compound.

EXAMPLE 28 2,3-dimethyl-6H-dibenz [b,f] [1,41oxazocin-11(12H)-one (a) Diazotization of 4,5 dimethyl-Z-nitroaniline followed by decomposition of the diazonium derivative in aqueous sulfuric acid gives 2-nitro-4,5-dimethylphenol.

(b) Employing sodium 2-nitro-4,5-dimethylphenolate in place of the sodium o-nitrophenate in Example 1(a) gives methyl o-(2-nitro4,5-dimethylphenoxy)methyl benzoate.

(c) When the product from (b) is substituted for the corresponding product in Example..1(.b) and the new product o-(2 nitro-4,5-dimethylphenoxy)methylbenzoic acid carried through procedure 1(d), there is/obtained 2, 3-dimethyl-6H-dibenz[b,f] [1,4] -oxazoein-1 1-( l2H)-one.

EXAMPLE 29 v i 12- 3- (4-hydroxypiperidyl propyl -2- trifluoromethyl 6H-dibenz-[b,f] [l,'4]oxazocin-11(12H)-one When the reaction of Example 24(b) is carried out with the exception that 20.2 g. of 4-hydroxypiperidine is substituted for the 2-piperazineethanol, there is obtained the desired compoun EXAMPLE 30 By substituting 22.8 g; of 4-aminoi'1iethylpiperidine for the 2-piperazineethanol in Example 24(b), there is obtained 12- [3- (4-aminomethylpiperidyl )propyl] -2- (trifiuoromethyl)-6H-dibenz[b,f] [1,4]oxazorin-1 1 12H )-one. What is claimed is:

1. A compound of the formula N ower alkylene piperidino, (lower.-alkoxy-)piperidino, hydroxypiperidino,

aminomethylpiperidino, pyrrol idino, (lowerf alkyl)pyralkanoyloxy(lower alkyl)piperazino wherein to 14 carbons, (hydroxy-lower alkyl)piperazino, (carbo-lower alkoxy)piperazino, homopiperazino or N -(2-hydroxy-lower alkyl) homopiperazino, n is 1 to 4, and physiologically acceptable acid addition salts thereof.

2. A,com pound as in claim 1 wherein R and R each is hydrogen and each R is lower alkyl.

3. Acompound as in claim 1 wherein R is hydrogen, R is chlorine, each R is lower alkyl and n is 1.

4. A compound as in claim 1 wherein each lower alkyl and the lower alkylene group has 2 '5. A compound as in claim 2 group is methyl carbons.

6. A compound as in claim 2 wherein each lower alkyl group is methyl and the lower alkylene group has 3 carbons.

7. A compound as in claim 1 wherein R and R each is hydrogen, (R N is hydroxyethylpiperazinyl and the lower alkylene group has 3 carbons.

8. A compound as in claim 1 wherein R and R each is hydrogen, (R N is methylpiperazinyl and the lower alkylene group has 3 carbons.

9. A compound as in claim 1 wherein R is hydrogen, R is trifluoromethyl, (R N is hydroxyethylpiperazinyl, the lower alkylene group has 3 carbons and n is 1.

References Cited FOREIGN PATENTS 6/1966 Germany OTHER REFERENCES Burger? Medicinal Chemistry, 2nd ed., pp. 72-8l (1960), (Interscience).

HENRY R. JILES, Primary Examiner R. BOND, Assistant Examiner:

US. Cl. X.R. 

